Probabilistic Points of Departure and Reference Doses for Characterizing Human Noncancer and Developmental/Reproductive Effects for 10,145 Chemicals

Abstract

Background: Regulatory toxicity values used to assess and manage chemical risks rely on the determination of the point of departure (POD) for a critical effect, which results from a comprehensive and systematic assessment of available toxicity studies. However, regulatory assessments are only available for a small fraction of chemicals.

Objectives: Using in vivo experimental animal data from the U.S. Environmental Protection Agency's Toxicity Value Database, we developed a semiautomated approach to determine surrogate oral route PODs, and corresponding toxicity values where regulatory assessments are unavailable.

Methods: We developed a curated data set restricted to effect levels, exposure routes, study designs, and species relevant for deriving toxicity values. Effect levels were adjusted to chronic human equivalent benchmark doses (${\text{BMD}}_h$). We hypothesized that a quantile of the ${\text{BMD}}_h$ distribution could serve as a surrogate POD and determined the appropriate quantile by calibration to regulatory PODs. Finally, we characterized uncertainties around the surrogate PODs from intra- and interstudy variability and derived probabilistic toxicity values using a standardized workflow.

Results: The ${\text{BMD}}_h$ distribution for each chemical was adequately fit by a lognormal distribution, and the 25th percentile best predicted the available regulatory PODs [$R^2\ge 0.78$, $\text{residual standard error}\left(\text{RSE}\right)\le 0.53$ ${\log }_{10}$ units]. We derived surrogate PODs for 10,145 chemicals from the curated data set, differentiating between general noncancer and reproductive/developmental effects, with typical uncertainties (at 95% confidence) of a factor of 10 and 12, respectively. From these PODs, probabilistic reference doses (1% incidence at 95% confidence), as well as human population effect doses (10% incidence), were derived.

Discussion: In providing surrogate PODs calibrated to regulatory values and deriving corresponding toxicity values, we have substantially expanded the coverage of chemicals from 744 to 8,023 for general noncancer effects, and from 41 to 6,697 for reproductive/developmental effects. These results can be used across various risk assessment and risk management contexts, from hazardous site and life cycle impact assessments to chemical prioritization and substitution. https://doi.org/10.1289/EHP11524.